Brain somatic mosaicism (BSM) refers to genome variation within brain cells that results from accumulated postzygotic mutations. These mutations can be used to understand cell lineage, molecular dynamics and disease processes. Unlike most other organs, brain cells are mostly fixed in position and not replaced throughout life. Thus, assessing mosaic variants (MVs) within the brain, including their spread and cell type-specific distributions and correlations with aging and cellular health, can reveal insights into neurodevelopmental, neuropsychiatric and neurodegenerative diseases. Extracting genetic material from human surgical brain resections, pregnancy remnants, or postmortem samples can reveal the origins of brain cells and uncover the effects of aging and disease on genomic integrity. Technological advances combining high-read-depth bulk sequencing, isolation of specific brain cell types, and single-cell multiomics can both detect and quantify MVs with good precision and recall. Research exploiting brain MVs is revolutionizing the understanding of the origins, mechanisms and potential treatments for brain conditions.